This P01 renewal application comes from an experienced research team that will investigate Barrett's esophagus (BE), the only established precursor to esophageal adenocarcinoma (EA), a highly lethal malignancy whose incidence increased more than 600 percent in three decades. BE is a unique in vivo model of human epithelial neoplasia, and the P01 theme of "neoplastic progression in Barrett's esophagus: pathways and prevention" emphasizes the translational research goals of the P01 for 1) cancer risk prediction, 2) modifiable risk and protective factors for cancer prevention and 3) individualized interventions tailored to risk in BE and other neoplasms whose early stages are less amenable to investigation. The study design is a prospective investigation of the Seattle BE Cohort, one of the largest and best characterized in the world. All data will be derived from this cohort, maintained by Core B (Clinical Research). Project 1 (Clonal Evolution) will investigate epigenetic and genomic instability and clonal evolution in BE to evaluate selected LOH, copy number change, CpG island methylation and DNA content abnormalities to determine the extent to which they predict neoplastic progression. Project 1 will develop clinically compatible DNA biomarker platforms for validated markers. Project 2 (Epidemiology) hypothesizes that obesity and reflux combine to increase risk of EA through a network of mechanisms, including metabolic abnormalities associated with the insulin resistance syndrome, inflammation and oxidative stress. It seeks to identify effective prevention strategies and develop a predictive risk model of neoplastic progression in BE that can be used clinically. Project 3 (Genetic Instability) will examine some of the earliest processes contributing to neoplasia in BE and hypothesizes that chronic inflammation and genotoxic stress predispose to telomere shortening and genetic instability at chromosomal fragile sites. The P01 is highly collaborative and all projects and cores interact. Clonal evolutionary markers, epidemiology assessments, and measures of instability provided by Projects 1, 2 and 3, respectively, are shared resources to advance common goals. These interactions are facilitated by Core C (Biostatistics and Evolutionary Analysis), which provides input into all study design as well as a framework for analysis of the complicated datasets of the projects. Core A (Leadership) provides a vehicle for inter project and core communications.